The invention relates to metabolites of the compound 2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyl-oxymethyl-2-oxo-ethyl]-isobutyramide, pharmaceutical compositions thereof, and to methods of using the metabolites and the pharmaceutical compositions in the treatment of diseases associated with reduced levels of growth hormone.
Growth hormone (GH), which is secreted from the pituitary gland, stimulates the growth of all tissues in the body that are capable of growing. Additionally, GH is known to mediate the following basic effects on the metabolic processes of the body:
(1) increased rate of protein synthesis in substantially all cells of the body;
(2) decreased rate of carbohydrate utilization in cells of the body; and
(3) increased mobilization of free fatty acids and use thereof for energy.
Deficiency in growth hormone production results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous GH has been shown to reverse many of these metabolic changes. Additional benefits of therapy have included reduction in LDL cholesterol and improved psychological well-being.
In cases where increased levels of GH were desired, the problem was generally solved by providing exogenous GH or by administering an agent which stimulated GH production or release. In either instance, the peptidyl nature of the compound necessitated that it be administered by injection. Initially, GH was obtained from extractions of the pituitary glands of cadavers. This resulted in an expensive product, and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the GH (e.g. Jacob-Creutzfeld Disease). Recently, recombinant GH has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be administered by injection or by nasal spray.
Most GH deficiencies are caused by defects in GH release, not primary defects in the pituitary synthesis of GH. Therefore, an alternative strategy for normalizing serum GH levels is by stimulating its release from somatotrophs. Increasing GH secretion can also be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of synthetic GH-releasing agents to stimulate pituitary GH secretion are being pursued, and may have several advantages over expensive and inconvenient GH replacement therapy. By acting along physiologic regulatory pathways, the most desirable agents would stimulate pulsatile GH secretion, and excessive levels of GH that have been associated with undesirable side effects of exogenous GH administration would be avoided by virtue of intact negative feedback loops.
Physiologic and pharmacologic stimulators of GH secretion include arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause GH to be released from the pituitary gland by acting in some fashion on the hypothalamus, perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GHRF), or an unknown endogenous GH-releasing hormone, or all three of these.
Other compounds have been developed which stimulate the release of exogenous GH such as analogous peptidyl compounds related to GHF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones, are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. Additional GH secretagogues are disclosed in, inter alia, commonly assigned PCT International Application Publication No. WO97/24369, the disclosure of which is incorporated herein by reference, which refers to certain GH secretagogues of Formula A: 
The instant invention provides metabolites of the compound of formula (I) 
the racemic-diastereomeric mixtures and optical isomers thereof, prodrugs thereof, and the pharmaceutically acceptable salts of the metabolites, racemic-diastereomeric mixtures, optical isomers, and prodrugs; pharmaceutical compositions thereof; and to methods of treating disease states associated with reduced levels of growth hormone using the metabolites and pharmaceutical compositions.